We propose to examine the impact of acute and chronic stress on the functional capacity of central noradrenergic neurons. Our studies may be divided into three groups:. (1) We wish to determine whether changes in tyrosine hydroxylase (TH) activity within locus coeruleus (LC) neurons during chronic cold stress are indicative of alterations in norepinephrine (NE) efflux. Release will be monitored using in vitro slices, in vivo voltammetry, and local perfusion in situ via dialysis tubing. The LC and two of its terminal fields will be examined, cerebellum and hippocampus will be examined. Among the questions to be studied are the following: Does acute, severe stress lead to an initial depletion of releasable NE? Does the activation of TH, which occurs within a few minutes of stimulation, increase the capacity for subsequent release? Does TH induction lead to a still greater capacity for release? (2) We wish to determine the extent to which increases in NE release during stress are due to alterations in the firing rate of LC neurons. We will record from LC neurons and determine the impact of stress on the firing rate of these cells. In addition, we will measure the amount of transmitter released from slices per impulse. (3) We wish to determine the degree to which adaptive changes occurring in central NE neurons in response to chronic stress affect the functioning of post-synaptic cells. We will record from single hippocampal granule cells and cerebellar Purkinje neurons during electrical stimulation of the LC to determine if exposure to chronic stress alters the inhibitory effect of release of endogenous NE on the spontaneous firing rates of these target neurons. In addition, electrical stimulation of glutaminergic, perforant path input to granule cells during electrical stimulation of the LC will be used to determine if exposure to chronic stress alters the modulatory effect of NE on other, non-NE inputs to target neurons. This work will be related to the basic neurobiology of monoaminergic neurons and their targets and to the relation between stress and depression.